10-hydroxy-2-phenyl-5h-pyrido(1,2-a)pyrimido(4,5-d)-pyrimidin-5-one and processes thereto

ABSTRACT

10 - HYDROXY - 2 - PHENYL - 5H-PYRIDO(1,2-A)PYRIMIDO(4,5-D)PYRIMIDIN-5-ONE AND THE ALKONOYL ESTER THEREOF ARE PREPARED BY THERMAL CYCLIZATION OF A 4-(2-AMINO3-PYRIDYLOXY) - 2 - PHENYL - 5 - PYRIMIDINECARBOXYLIC ACID, ALKYL ESTER OR OF 4-((3-HYDROXY-2 - PYRIDYL)AMINO) - 2 PHENYL-5-PYRIMIDINECARBOXYLIC ACID, OR THE ESTER THEREOF.

Sept. 11, 1914 D. H. KIM EI'AL 3,836,533

10 -unm0xy z; -lHLJNYL-5Ij-PYR'IDO '1 2" PYRIMIDO [4, 5-31PYRIMIDIN-B-ONE AND PROCESSES THERETO Filed Oct. 30. 1972 9 r 9 I CORCOR 0 N A N/ B N N s s N Cl N o c n N N United States Patent ClaimsABSTRACT OF THE DISCLOSURE Hydroxy 2 phenyl 5 I I-pyrido[l,2-a]pyrimido[4,5-d] pyrimidin-S-one and the alkanoyl esterthereof are prepared by thermal cyclization of a 4-(2-amino-3-pyridyloxy) 2 phenyl S pyrimidinecarboxylic acid, alkyl ester or of4-[(3-hydroxy-2 pyridyl)amino] 2 phenyl-S-pyrimidinecarboxylic acid, orthe ester thereof.

This invention relates to 10 hydroxy 2 phenyl 5E- pyrido[1,2aJpyrimido[4,5-d]pyrimidin 5 one and the lower alkanoyl esters thereof.Also contemplated are intermediates thereto and processes for theproduction thereof.

In its principal aspect, the invention sought to be patented comprisescompounds of the structural formula:

wherein R is hydrogen or lower alkanoyl. Said compounds (I) exert adepressant action on the central nervous system as demonstrated byevaluation in standard pharmacological test procedures.

In yet another aspect, the invention comprises compounds of the formula:

wherein R is lower alkyl; R is hydrogen or lower alkyl; and R ishydrogen or lower alkanoyl; with the proviso that when R is hydrogen, Rcan only be hydrogen.

In still another aspect, the invention provides a process for thepreparation of 10-hydroxy-2phenyl-SE-pyrido[1,2-a]pyrimido[4,5-d1pyrimidin-5-one in which a 4 (2-amino-3-pyridyloxy) 2 phenyl-S-pyrimidinecarboxylic acid, (lower)alkylester is heated at a temperature ranging from about 160 C. to about 260C. A temperature ranging from about 190 C. to about 230 C. is preferred.

The production of 10 hydroxy-2-phenyl SE-pyrido [l,2-a]pyrimido[4,5d1pyrimidin 5 one (V) and the lower alkanoyl esters thereof (VI) areillustrated schematically in FIG. I of the accompanying Drawing. In FIG.I, R is lower alkyl and R is lower alkanoyl.

Referring now to FIG. I, the starting material for the II III Icesynthesis depicted therein is a 4-chloro-5-carb (lower)alkoxy 2phenylpyrimidine (IV). Step A is effected by treating compound IV with2-amino-3-hydroxypyridine in a lower alkanol (absolute) in the presenceof metallic sodium, which affords a 4-(2 amino 3 pyridyloxy)-2- phenyl 5pyrimidinecarboxylic acid, (lower)alkyl ester (II). In Step B compoundII is cyclized to give 10-hydroXy 2-phenyl-5 II-pyrido[1,2-a]pyrimido[4,5-d1pyrimidin 5 one (V) by heating at atemperature ranging from about C. to about 260 C., preferably about C.to about 230 C. Alkanoylation of compound (V) to yield the correspondingester (VI) is effected by reaction with a conventional acylating agent,such as a lower alkanoic acid chloride or anhydride.

Compound V can alternatively be obtained in two steps from compound IIas follows: In Step D, compound II is heated in a lower alkanol atreflux temperatures to give a 4 [(3 hydroxy 2 pyridyl)amino]-2-phenyl-S-pyrimidinecarboxylic acid, (lower)alkyl ester (VII). In Step E,compound VII is thermally cyclized by heating at a temperature rangingfrom about 160 C. to about 260 C., preferably about 190 C. to about 230C.

Compound VI can, alternatively, be obtained by cyclization of eithercompound VIII (Step G) or compound IX (Step I). In Step G, thecyclization is effected by heating compound VIII in a lower alkanoicacid anhydride at reflux temperatures. In Step I, the cyclization iseffected by heating compound IX at a temperature rang ing from about 160C. to about 260 C., preferably about 190 C. to about 230 C. CompoundVIII is prepared either from compound II (Step I) or from com pound VII(Step F) by hydrolysis with aqueous sodium hydroxide followed byacidification. Compound IX is prepared from compound VII (Step H) byalkanoylation with a lower alkanoic acid chloride or anhydride.

Compound VIII can also be obtained (Step K) by hydrolysis of compound Vwith aqueous sodium hydroxide followed by acidification.

The starting materials employed in the aforedescribed processes areeither known compounds or can be prepared from known compounds byconventional methods.

As used herein and in the claims the terms lower alkanoyl and loweralkanoic acid contemplate such groups in which the alkyl moiety thereofis a methyl, ethyl, propyl, or isopropyl group. The term lower alkylmeans the methyl, ethyl, propyl or isopropyl group.

When the compounds of the invention are employed as depressants of thecentral nervous system, they may be administered alone or in combinationwith pharmaceutically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compound, chosenroute of administration, and standard pharmaceutical practice. Forexample, they may be administered orally in the form of tablets orcapsules containing such excipients as starch, lactose, magnesiumstearate, and so forth. They may be administered orally in the form ofsolution or they may be injected parenterally, e.g. intramuscularly. Forparenteral administration, they may be used in the form of a sterilesolution or suspensions containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present pharmacologically active agents will vary withthe form of administration and the particular compound chosen.Furthermore, it will vary with the particular subject under treatment.Generally, treatment is initiated with small dosages substantially lessthan the optimum dose of the compound. Thereafter, the dosage isincreased by small increments until the optimum effect under thecircumstances is reached. It will generally be found that when thecomposition is administered orally, larger quantities of the activeagent will be required to produce the same effect as a smaller quantitygiven parenterally. In general, the compounds. of this invention aremost desirably administered at a dosage level that will generally afiordefiective results without causing any harmful or deleterious sideeifects.

The following examples illustrate the manner and process for making andusing the invention:

EXAMPLE I 4-(2-Amino-3-Pyridyloxy)-2-Phenyl-5-Pyrimidine- CarboxylicAcid, Ethyl Ester Sodium (1.1 g.) is dissolved in absolute ethanol (170ml.). To the solution at room temperature is added with stirring over a10 minute period 2-arnino-3-hydroxypyridine (5.6 g.). 4 Chloro 5carbethoxy-Z-phenylpyrimidine (13 g.) is added, and the mixture isheated gently for 30 minutes. The mixture is chilled causingprecipitation of a solid which is collected and washed with ethanol andthen Water to aflord 13 g. of the title compound, m.p. 151153 C.Recrystallization from ethanol gives a sample, m.p. 152-154" C.

Analysis for C H N O .-Calculated: C, 64.27; H, 4.80; N, 16.66. Found:C, 63.93; H, 4.85; N, 16.88.

EXAMPLE II 4- 3-Hydroxy-2-Pyridyl) Amino]-2-Phenyl-5Pyrimidine-Carboxylic Acid, Ethyl Ester A mixture of4-(2-amino-3-pyridyloxy)-2-phenyl-5 pyrimidinecarboxylic acid, ethylester (1.5 g.) and ethanol (100 ml.) is heated under reflux for 6 hours,treated with activated charcoal, and filtered. Chilling of the filtratein ice causes separation of a precipitate which is collected andrecrystallized from absolute ethanol to give 0.5 g. of the titlecompound, m.p. 179-181 C.

Analysis for C H N O .Calculated: C, 64.27; H, 4.80; N, 16.66. Found: C,64.45; H, 4.75; N, 16.45.

EXAMPLE III 4- (3-Hydroxy-2-Pyridyl) Amino]-2-Phenyl-5-Pyrimidine-Carboxylic Acid, Ethyl Ester, Acetate To a pyridine solution (50 ml.)containing 4-[(3- hydroxy-2-pyridyl)amino]-2-phenyl 5pyrimidinecarboxylic acid, ethyl ester (3.3 g.) is added dropwise aceticanhydride (1.2 g.). The resulting mixture is heated under reflux for 20minutes. The excess pyridine is removed under reduced pressure to givean oily residue which solidifies on standing. The solid is trituratedwith Water, and then recrystallized from ethanol to give 3.5 g. of thetitle compound, m.p. 99-101.5 C.

Analysis for C H N O .Calculated: C, 63.48; H, 4.80; N, 14.81. Found: C,63.57; H, 4.95; N, 14.70.

EXAMPLE IV 4-[ (3-Hydroxy-2-Pyridyl) Amino]-2-Phenyl-5-Pyrimidine-Carboxylic Acid A. From4-(2-amino-3-pyridyloxy)-2phenyl-5-pyrimidinecarboxylic acid, ethylester.

Alkaline hydrolysis of 4-(2-amino-3-pyridyloxy)-2-phenyl-S-pyrimidinecarboxylic acid, ethyl ester (15% aqueous sodiumhydroxide) and subsequent acidification alfords the title compound in anear quantitative yield. Recrystallization from dimethylformamide (DMF)affords a sample, m.p. 246249 C.

Analysis for C H N O .-C'alculated: C, 62.33; H, 3.92; N, 18.18. Found:C, 61.74; H, 4.00; N, 18.57.

B. From 4-[(3-hydroxy-2-pyridyl) amino]-2-phenyl 5- pyrimidinecarboxylicacid, ethyl ester.

Alkaline hydrolysis of 4-[(3-hydroxy 2 pyridyl)amino]-Z-phenyl-S-pyrimidinecarboxylic acid ethyl ester aifords thetitle compound in a quantitative yield, m.p. 243-245 C.

C. From l-hydroxy-2-phenyl-SE-pyrido[1,2-a]pyrimido[4,5-]pyrimidin--one.

A mixture of 10-hydroxy-2-phenyl-5E-pyrido[1,2-a]pyrimido[4,5-d1pyrimidin-5-one (3.2 g.), 20% aqueous sodium hydroxidesolution (30 ml.), and ethanol (15 ml.) is heated under reflux for 20minutes, neutralized with concentrated hydrochloric acid and then madeacidic with dilute hydrochloric acid. The precipitate is collected andWashed with water to give the title compound, m.p. 245 dec.

EXAMPLE V 10-Hydroxy-2-Phenyl-5I-Pyrido[ 1,2-a] Pyrimido- [4,5 -d]Pyrimidin-S-One A. 4-(2Amino-3-pyridyloxy)-2-phenyl-5-pyrimidinecarboxylic acid, ethyl ester(1.0 g.) is heated at 210 C. for 2 0 minutes. After cooling toroomtemperature, the solid cake is recrystallized from dimethylformamide(DMF) to give 0.9 g. of the title compound, m.p. 261- 263 C.

Analysis for C H N O .Calculated: C, 66.20; H, 3.47; N, 19.30. Found: C,66.39; H, 3.30; N, 19.42.

B. 4-[(3-Hydroxy 2 pyridyl)amino]-2-phenyl-5- pyrimidinecarboxylic acid,ethyl ester (0.4 g.) is heated at 200 C. i10 C. for 7 minutes. The solidcake thus obtained melts at 256 C. The mixture melting point With thesample prepared by method A is not depressed. The infrared spectrum ofthe compound is identical with that of the sample prepared by method A.

EXAMPLE VI 10-Hydroxy-2-Phenyl-5 g-Pyrido[ 1,2-a] Pyrimido [4,5 -dPyrimidin-S-One, Acetate A. From IO-hydroxy 2 phenyl 5g-pyrido[1,2-a]pyrimido[4,5-d1pyrimidin-5-one.

A mixture of lO-hydroxy 2 pheny-Sfl-pyridoUJ-a] pyrimid0[4,5-d]pyrimidin5 one (1.8 g.) and acetic anhydride (60 ml.) is heated under reflux for1.5 hours, then chilled in ice. The precipitate is collected, giving 2.0g. of the title compound, m.p. BUS-308 C.

Analysis for C H N.,O .Calculated: C, 65.05; H, 3.64; N, 16.86. Found:C, 64.88; H, 3.91; N, 16.50.

B. From 4-[(3-hydroxy 2 pyridyl)amino]-2-phenyl- 5-pyrimidinecarboxylicacid.

A mixture of4-[(3-hydroxy-2-pyridyl)aminoJ-Z-phenyl5-pyrimidinecarboxylic acid (2.6g.) and acetic anhydride (30 ml.) is refluxed gently for 1.5 hours. Asolid is removed by filtration. Chilling of the filtrate causesseparation of a precipitate which is collected and recrystallized fromacetic anhydride to give the title compound, m.p. 293 C. (dec.). Theinfrared spectrum of this compound is identical With that of a sampleprepared by method A.

C. From 4-(3-hydroxy 2 pyridylamino)-2-phenyl-5- pyrimidinecarboxylicacid, ethyl ester, acetate.

4-(3-Hydroxy 2 pyridylamino)-2-phenyl-5-pyrimidine-carboxylic acid,ethyl ester, acetate (0.6 g.) is heated at 2201-5 C. for 15 minutes. Thesolid cake is recrystallized from dimethylformamide to afford the titlecompound, m.p. 293-296 C. A mixture m.p. with a sample prepared bymethod A is not depressed.

EXAMPLE VII -A compound of Formula I is administered orally (P.O.) orintraperitoneally (LR) to each of three mice. The animals are observedfor signs of CNS-depressant ac tivity, such as decreased motor activity,sedation, ataxia, loss of righting reflex, and decreased respiration.When tested as above-described, l0 hydroxy2-pheny-5gpyrido[1,2-a]pyrimido[4,5 d]pyrimidin-5-one exhibiteddecreased motor activity and decreased respiration at 400 mg./ kg.(P.O.); the acetate of said compound exhibited decreased motor activity,sedation-ataxia, ataxia, and decreased respiration at 127 rug/kg. (LR)and loss of righting reflex at 400 mg./ kg. (I.P.).

5 6 What is claimed is: t 4. A process for the preparation of10-hydroxy-2-phen- 1. A compound of the formula yl 5Epyrido[1,2-a]pyrimido[4,5-d1pyrimidin-5-one in which a4-(2-arnino-3-pyridyloxy)-2-phenyl 5 pyrimidinecarboxylic acid,(lower)a1kyl ester is heated at a 0 A I N temperature ranging from about160 C. to about 230 C. N 5 5. A process as defined in Claim 4 in whichthe term- I I J perature range is about 190 C. to about 230 C. Q N NReferences Cited CA. 46: 8127d (1952), Matsukawa et a1., abstract of I.

10 Pharm. Soc., Japan, 71: 14237.

wherein R is hydrogen or lower alkanoyl.

2. The compound as defined in Claim 1, which is 10- NATALIE TROUSOF,Primary Examiner y f 2 phenyl 5E pyndo[lz'amynmldoms'd] S. D. WINTERS,Assistant Examiner pyrrmrdm-S-one.

3. The compound as defined in Claim 1, which is 10- 15 U S C1 XR hydroXy2 phenyl 5g pyrido[l,2-a]pyrimido[4,5-d] pyrimidinme, mama 260-2564 (3,251 R, 256.4 N, 296 R; 424 251

